Rheumatoid arthritis (RA) is an immune-mediated disease with synovial inflammation and invasion of the extracellular matrix. While adaptive immunity plays a key role in the pathogenesis of RA, the contribution of innate immune responses has been increasingly appreciated in recent years. We propose that the IKK-related kinases, IKKi and TBK1, play a key role in innate immune responses in the joint and modulate synovial inflammatory responses. The IKK-related kinases are homologous to the classic IKK complex, which regulates NF-kB and pro-inflammatory gene expression. However, the functions of IKKi and TBK1 are primarily mediated by interferon regulatory factors (IRFs) after TLR ligation and regulate a distinct set of genes implicated in RA. The kinases appears to play a key role in the expression IRFS and c-Jun regulated genes, including IFNbeta and chemokines like RANTES. Preliminary studies demonstrated that functional activity of the IKK-related kinase complex in cultured synoviocytes is rapidly increased by TNFalpha and TLR agonists. We have also shown that IRFS is activated in RA synovium, which represents an early step IFNbeta and RANTES expression due to . Additional preliminary data with human FLS suggest that the IKKi pathway can activate other signaling cascades, such as c-Jun, that play a role in assembly of the interferon ehanceosome. Preliminary data also show that IKKi inhibition in a murine arthritis model can suppress synovial inflammation and articular IFNbeta production. Because the function and hierarchy of IKKi and TBK1 are frequently cell lineage specific, we propose to study how these kinases individually contribute to synoviocyte gene expression and synovitis. We hypothesize that IKKi and, to a lesser extent TBK1, serve as signaling pathways for activation of innate immunity in RA and contribute to disease activity. To explore this possibility we will 1) determine the role of IKKi and TBK1 in animal models of arthritis; 2) determine the function and regulation of IKKi and TBK1 in synovial tissue and synoviocytes; and 3) determine the signal transduction pathways that regulate innate immune responses through activation of IKKi and TB1 in synoviocytes. These experiments will provide insight into IKK-related kinases and pathogenic mechanisms that contribute to synovitis and joint destruction. [unreadable] [unreadable] [unreadable]